Nucleolar activity in neurodegenerative diseases: a missing piece of the puzzle?

Abstract

Nucleoli are the sites where synthesis of rRNA and ribosomal assembly take place. Along with these "traditional" roles, the nucleolus controls cellular physiology and homeostasis. The cellular and molecular alterations associated with impaired nucleolar activity ("nucleolar stress") have just started to be systematically explored in the nervous system taking advantage of newly available animal models lacking rRNA synthesis in specific neurons. These studies showed that nucleolar function is necessary for neuronal survival and that its modality of action differs between and within cell types. Nucleolar function is also crucial in pathology as it controls mitochondrial activity and critical stress signaling pathways mimicking hallmarks of human neurodegenerative diseases. This mini-review will focus on the modes of action of nucleolar stress and discuss how the manipulation of nucleolar activity might underscore novel strategies to extend neuronal function and survival.Keywords rRNA . Nucleolus . Cellular stress . Neurodegeneration . Mouse models Non-traditional roles of the nucleolus under physiological conditionsNucleoli are non-membrane-bound structures within the nucleus where ribosomal RNA (rRNA) genes are transcribed.These atypical cellular organelles consist of three major compartments with specific functions: (1) fibrillar centers (FC, pre-rRNA synthesis), (2) dense fibrillar components (DFC, pre-RNA processing), and (3) granular components (GC, ribosome assembly). Their organization allows hosting a number of proteins and RNAs with an important role in various cellular processes. Thus the perturbation of nucleolar dynamic assembly exerts profound effects on several cellular functions [1]. A detailed description of nucleolar morphology and organization has been provided elsewhere [1,2]. Here we focus on the mechanisms by which nucleolar activity may regulate neuronal function and survival and contribute especially to neurodegenerative diseases.One intriguing mechanism to control embryonic development, differentiation, and survival is the nucleolar shuttling of cell cycle regulators and transcription factors dictating cell lineage to the nucleoplasm [1]. Moreover, rRNA repression seems required for the execution of differentiation programs. For example, during the embryonic development, transcription of rRNA genes is repressed by lineage-commitment transcription factors turning off the pluripotency genes [3]. During neural lineage commitment there is no direct evidence that rRNA transcription is inhibited; it is likely, however, that mechanisms involving nucleolar dynamics could be in play. For example in brain and retina the levels of the nucleolar protein nucleostemin, a controller of pre-rRNA processing, are rapidly reduced before cell cycle exit and neural differentiation [4,5], suggesting that rRNA biosynthesis may have a regulatory effect on neurogenesis.However, the major regulatory function associated with altered dynamics of nucleolar proteins is connected to the stress response and involv...

Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome

“…UBF encoded by UBTF (upstream binding transcription factor, RNA polymerase I gene) is associated with NOR and is required for rDNA transcription by RNA polymerase 1 (83). It is known that altered expression of nucleolar chaperones and factors involved in rRNA synthesis results in nucleolar stress which in turn leads to impaired ribosomal biogenesis (4,58,69,79). The present observations show nucleolar stress in the hippocampus, mainly in CA1 but also in DG, in AD.…”

Regulation of nucleolus assembly by non-coding RNA polymerase II transcripts

“…76 Accordingly, there is a renewed interest for using the nucleolus as a potential target for therapeutic treatments of cancer and other diseases. 77,78 It becomes clear that further elucidating the regulation of RNA-protein interactions is crucial to understand the mechanisms underlying the assembly dynamics and the activities of the nucleolus as well as those of other nuclear bodies.…”

Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

“…AEG-1 colocalization with fibrillarin, a dense fibrillar component of the nucleolus participating in ribosome synthesis (Ochs et al , 1985), indicates that AEG-1 may play a role in pre-ribosomal RNA processing in response to oxidative stress, a hallmark of all neuroinflammatory and neurodegenerative disorders including biological aging. Disrupted nucleolar integrity and impaired ribosomal RNA synthesis were observed in aging and neurodegenerative diseases (Parlato and Kreiner, 2013). We recently investigated whether oxidative stress affected AEG-1 sub-cellular localization in human astrocytes.…”

“…5E–H). The nucleolus senses stress and is a central hub for coordinating stress responses, leading to changes in its organization and composition (Parlato and Kreiner, 2013). Hence, the present finding of oxidative stress-induced AEG-1 colocalization with fibrillarin, within human astrocyte nuclei, is vital for further comprehending cellular stress response pathways.…”